KR20180011830A - New method for preparation of chromanone derivatives - Google Patents
New method for preparation of chromanone derivatives Download PDFInfo
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- C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
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- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
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Abstract
Description
본 발명은 5,7-디플루오로크로만-4-온 유도체의 신규한 제조방법에 관한 것이다. The present invention relates to a novel process for the preparation of 5,7-difluorochroman-4-one derivatives.
크로마논 유도체는 의약 및 화학 분야에서 물질 그 자체, 또는 물질 합성 과정 등에 매우 다양하게 이용되는 물질이다. 그런데, 크로마논 유도체의 중요성에도 불구하고, 이를 손쉽게 합성하는 방법은 많이 보고되고 있지 않다. Chromanone derivatives are substances that are widely used in the fields of medicine and chemistry itself or in the process of synthesizing substances. However, despite the importance of chromanone derivatives, no method has been reported to easily synthesize them.
국제공개공보 WO 2009/156072호에는 3,5-디플루오로페놀을 출발물질로 사용하여 5,7-디플루오로크로만-4-온을 제조하는 방법이 개시되어 있다. 상기 문헌에는 3,5-디플루오로페놀과 3-클로로-1-프로판올의 O-알킬화 반응을 수행하고, 산화크롬(VI)을 시약으로 사용하여 산화반응을 진행한 후, 마지막으로 옥살릴 클로라이드와 알루미늄 트리클로라이드를 시약으로 고리화 반응을 진행하여 총 60 %의 수율로 5,7-디플루오로크로만-4-온을 제조하는 방법이 개시되어 있다. International Publication WO 2009/156072 discloses a process for preparing 5,7-difluorochroman-4-one using 3,5-difluorophenol as a starting material. In this document, an O-alkylation reaction of 3,5-difluorophenol and 3-chloro-1-propanol is carried out and the oxidation reaction is carried out using chromium oxide (VI) as a reagent. Finally, oxalyl chloride And aluminum trichloride as a reagent to produce 5,7-difluorochroman-4-one in a total yield of 60%.
그러나, 상기 문헌에 기재된 제조방법은 각 단계마다 실리카겔 상의 컬럼 크로마토그래피 정제가 필요하여, 공업적인 대량합성의 공정에는 적합하지 않다. 또한, 산화크롬(VI) 시약을 사용한 산화반응을 통해 3-(3,5-디플루오로페녹시)프로판산을 제조하는 과정에서, 환경규제가 심한 중금속 산화제 산화크롬(VI)을 사용하기 때문에, 해당 공정은 대량생산 시 매우 부적절하다. 아울러, 상기 반응에서 사용하는 용매는 출발물질 대비 150 배 정도로 반응 후 폐액 처리로 인한 비용이 추가로 드는 문제점이 있다. 즉, 상기 문헌에 기재된 방법에 따르면, 제조원가가 높아지고 환경 규제가 심한 중금속을 사용하는 문제점이 있어, 대량생산에 적합한 공정이 아니다. However, the production process described in the above literature requires purification by column chromatography on silica gel for each step, which is not suitable for industrial mass-synthesis processes. Further, in the process of producing 3- (3,5-difluorophenoxy) propanoic acid through an oxidation reaction using a chromium (VI) reagent, heavy metal oxidizing agent chromium oxide (VI) , The process is very inadequate for mass production. In addition, the solvent used in the reaction has a problem that the cost due to the waste solution treatment after the reaction is about 150 times as much as the starting material. That is, according to the method described in the above document, there is a problem in that a manufacturing cost is increased and a heavy metal having severe environmental regulations is used, which is not suitable for mass production.
또한, 3,5-디플루오로페놀과 아크릴로니트릴을 출발물질로 하여 5,7-디플루오로크로만-4-온을 제조하는 방법이 국제공개공보 WO 2005/016896호에 개시되어 있다. 상기 문헌에는 3,5-디플루오로페놀과 아크릴로니트릴로 마이클 반응을 수행하여, 35 %의 수율로 3-(3,5-디플루오로페녹시)프로피오니트릴을 제조하였다. 다음으로 진한 염산으로 가수분해를 진행하여 3-(3,5-디플루오로페녹시)프로피온산을 76 %의 수율로 제조한 후, 마지막으로 티오닐 클로라이드를 이용하여 고리화하여 5,7-디플루오로크로만-4-온을 73 %의 수율로 제조하였다. 그러나, 상기 문헌에 기재된 제조방법 역시 실리카겔 상의 컬럼 크로마토그래피로 정제하여 일반적으로 공업적인 대량합성의 공정에는 적합하지 않다. 또한, 마지막 공정에서 -65 ℃까지 냉각하는 공정이 필요하기 때문에 실생산에 적용할 수 없는 문제점이 있다. Also, a method for producing 5,7-difluorochroman-4-one using 3,5-difluorophenol and acrylonitrile as starting materials is disclosed in International Publication No. WO 2005/016896. In this document, 3- (3,5-difluorophenoxy) propionitrile was prepared in a yield of 35% by performing a Michael reaction with 3,5-difluorophenol and acrylonitrile. Hydrolysis was then carried out with concentrated hydrochloric acid to give 3- (3,5-difluorophenoxy) propionic acid in a yield of 76%, and finally cyclized using thionyl chloride to give 5,7-di Fluorochroman-4-one was prepared in 73% yield. However, the preparation methods described in the above documents are also refined by column chromatography on silica gel and are generally not suitable for industrial mass-synthesis processes. In addition, since a step of cooling to -65 占 폚 is required in the last step, there is a problem that this method can not be applied to practical production.
이에 따라, 낮은 제조 원가를 가지며 통상적으로 사용 가능한 시약과 용매를 사용하여, 산업적으로 대량생산이 가능하고 환경 규제도 받지 않는 의약 및 화학 분야에서 매우 중요한 약물 특이 분자단인 5,7-디플루오로크로만-4-온을 대량생산할 수 있는 신규한 제조방법이 필요한 실정이다. As a result, it is possible to produce 5,7-difluoro-5-methyl-2-pyrrolidone, which is a drug-specific molecule, which is very important in medicine and chemistry fields, which can be industrially mass- There is a need for a novel production method capable of mass production of chroman-4-one.
본 발명은 별도의 정제 공정이 필요하지 않고 낮은 제조 원가를 가지며, 통상적으로 사용 가능한 시약과 용매를 사용하여 산업적으로 대량생산이 가능하고 제법상 환경 규제도 받지 않는 우수한 5,7-디플루오로크로만-4-온 유도체의 제조방법을 제공하고자 한다.It is an object of the present invention to provide an excellent 5,7-difluoroquinolone which does not require a separate purification step, has a low production cost, can be industrially mass-produced using commercially available reagents and solvents, 4-one derivatives of the general formula (I).
위 과제를 해결하기 위하여, 본 발명은 5,7-디플루오로크로만-4-온의 새로운 제조방법을 제공한다. 이하에서는 이에 대하여 상세히 설명한다.In order to solve the above problems, the present invention provides a novel process for producing 5,7-difluorochroman-4-one. Hereinafter, this will be described in detail.
본 발명은, 하기 화학식 I로 표시되는 화합물로부터 화학식 II로 표시되는 화합물을 제조하는 단계; 및 화학식 II로 표시되는 화합물을 고리화 반응시켜 화학식 III로 표시되는 화합물을 제조하는 단계를 포함하는, 화학식 III로 표시되는 화합물의 제조 방법을 제공한다:The present invention relates to a process for preparing a compound represented by the formula (II) from a compound represented by the formula (I): And a step of subjecting a compound represented by formula (II) to a cyclization reaction to prepare a compound represented by formula (III): < EMI ID =
[화학식 I](I)
[화학식 II]≪ RTI ID = 0.0 &
[화학식 III](III)
본 발명의 제조방법은 별도의 정제 공정이 필요하지 않고 낮은 제조 원가를 가지며, 환경 규제도 받지 않는 통상적으로 사용 가능한 시약과 용매를 사용하여 5,7-디플루오로크로만-4-온 유도체를 효과적으로 대량 생산할 수 있다. The production method of the present invention is characterized in that a 5,7-difluorochroman-4-one derivative is obtained by using a commercially available reagent and a solvent which do not require a separate purification step, have a low production cost, It can be mass-produced effectively.
본 발명의 일 구체예에 따르면 본 발명은, 화학식 I로 표시되는 화합물과 하기 화학식 IV로 표시되는 화합물을 반응시켜 하기 화학식 V로 표시되는 화합물을 제조하는 단계; 및 화학식 V로 표시되는 화합물에 2-요오드화벤조산(2-Iodobenzoic acid) 및 포타슘 퍼옥시모노설페이트(Potassium peroxymonosulfate)를 반응시켜 화학식 II로 표시되는 화합물을 제조하는 단계를 포함하는 화학식 II로 표시되는 화합물의 제조 방법을 제공한다. According to one embodiment of the present invention, there is provided a process for preparing a compound represented by the formula (V), comprising: reacting a compound represented by the formula (I) and a compound represented by the formula (IV) And a step of reacting a compound represented by the formula (II) and a compound represented by the formula (V) with 2-iodobenzoic acid and potassium peroxymonosulfate to prepare a compound represented by the formula (II) Of the present invention.
[화학식 IV](IV)
[화학식 V](V)
상기 화학식 IV에서, In the above formula (IV)
X는 할로겐 원자로 플루오로, 염소 또는 요오드로부터 선택될 수 있다. X can be selected from fluoro, chloro or iodo as halogen atoms.
상기 화학식 I로 표시되는 화합물과 화학식 IV로 표시되는 화합물을 반응시켜 화학식 V로 표시되는 화합물을 제조하는 단계에서, 반응은 O-알킬화 반응으로써 유기 용매로 테트라하이드로퓨란, 디옥산, 디클로로메탄, 1,2-디메톡시에탄, 디메틸포름아미드(DMF), 디메틸설폭사이드(DMSO) 등을 단독으로 또는 혼합하여 사용할 수 있고, 바람직하게 디메틸포름아미드를 사용할 수 있다. In the step of reacting the compound represented by the formula (I) with the compound represented by the formula (IV) to prepare the compound represented by the formula (V), the reaction is carried out by O-alkylation reaction with an organic solvent such as tetrahydrofuran, dioxane, dichloromethane, , Dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the like can be used alone or in combination. Dimethylformamide is preferably used.
또한, O-알킬화 반응에서 사용되는 염기는 수소화칼륨, 수소화나트륨, 수소화리튬, 포타슘 t-부톡사이드(potassium t-butoxide) 등을 사용할 수 있고, 바람직하게, 수소화나트륨을 사용할 수 있다. The base used in the O-alkylation reaction may be potassium hydride, sodium hydride, lithium hydride, potassium t-butoxide or the like, preferably sodium hydride.
상기 유기 용매 하에 화학식 I로 표시되는 화합물 및 염기는 10 ℃ 이하, 바람직하게는 0 내지 10 ℃에서 교반된 후, 화학식 IV로 표시되는 화합물과 혼합되어 60 내지 90 ℃에서 O-알킬화 반응이 수행될 수 있다. In the organic solvent, the compound represented by the formula (I) and the base are stirred at 10 ° C or lower, preferably 0 ° C to 10 ° C, and then mixed with the compound represented by the formula (IV) to carry out an O-alkylation reaction at 60 to 90 ° C .
상기 화학식 IV로 표시되는 화합물에 있어서, X는 염소인 것이 바람직하다. In the compound represented by the above formula (IV), it is preferable that X is chlorine.
상기 화학식 V로 표시되는 화합물에 2-요오드화벤조산(2-Iodobenzoic acid) 및 포타슘 퍼옥시모노설페이트(Potassium peroxymonosulfate)를 반응시켜 화학식 II의 화합물을 제조하는 단계에서, 반응은 극성 용매, 예컨대, 물, 메탄올, 아세토니트릴 또는 이의 혼합 용매를 사용한다. In the step of reacting a compound represented by the formula (V) with 2-Iodobenzoic acid and potassium peroxymonosulfate to prepare a compound of formula (II), the reaction is carried out in a polar solvent such as water, Methanol, acetonitrile or a mixed solvent thereof is used.
극성 용매 하에 화학식 V로 표시되는 화합물은 2-요오드화벤조산(2-Iodobenzoic acid) 및 포타슘 퍼옥시모노설페이트(Potassium peroxymonosulfate)와 60 내지 90 ℃에서 반응이 수행될 수 있다.In the polar solvent, the compound represented by the formula (V) can be reacted with 2-iodobenzoic acid and potassium peroxymonosulfate at 60 to 90 ° C.
상기 반응은 기존에 알려진 반응들과 달리 환경 오염에 따른 규제 시약이 아닌 일반적으로 위험부담 없이 사용 가능한 2-요오드화벤조산(2-Iodobenzoic acid) 및 포타슘 퍼옥시모노설페이트(Potassium peroxymonosulfate)을 사용함으로써 대량생산 공정에 적합하며 높은 제조 수율을 나타낸다.Unlike the known reactions, the above reaction is not a regulatory reagent due to environmental pollution. Generally, by using 2-Iodobenzoic acid and potassium peroxymonosulfate, which can be used without any risk, Process and shows a high production yield.
또한, 본 발명의 다른 구체예에 따르면 본 발명은, 화학식 I로 표시되는 화합물을 수산화구리를 이용하여 아크릴로니트릴과 반응시켜 하기 화학식 VI로 표시되는 화합물을 제조하는 단계; 및 화학식 VI로 표시되는 화합물을 가수분해하여 화학식 II로 표시되는 화합물을 제조하는 단계를 포함하는 화학식 II로 표시되는 화합물의 제조 방법을 제공한다. According to another embodiment of the present invention, there is provided a process for preparing a compound represented by the formula (VI), comprising reacting a compound represented by the formula (I) with acrylonitrile using copper hydroxide to prepare a compound represented by the formula (VI) And hydrolyzing the compound represented by the formula (VI) to prepare a compound represented by the formula (II).
[화학식 VI](VI)
상기 화학식 I로 표시되는 화합물을 수산화구리를 이용하여 아크릴로니트릴과 반응시켜 화학식 VI로 표시되는 화합물을 제조하는 단계에 있어서, 상기 반응은 마이클 부가 반응으로써 염기로 수산화구리를 사용하여 반응이 수행된다. 본 반응은 마이클 부가 반응에서 수산화구리를 사용함으로써 타 염기원을 사용하는 것과 대비하여 반응 수율을 크게 향상시킨다. In the step of reacting the compound represented by the formula (I) with acrylonitrile using copper hydroxide to prepare a compound represented by the formula (VI), the reaction is carried out by using Michael hydroxide as a base and copper hydroxide as a base . This reaction greatly improves the reaction yield by using copper hydroxide in the Michael addition reaction as compared with the use of a different base.
화학식 VI로 표시되는 화합물을 제조하는 단계는 75 내지 85 ℃에서 수행되는 것이 바람직하다.The step of preparing the compound represented by the formula (VI) is preferably carried out at 75 to 85 캜.
상기 화학식 VI로 표시되는 화합물을 가수분해하여 화학식 II로 표시되는 화합물을 제조하는 단계에 있어서, 산 또는 염기의 존재 하에 가수분해를 통해 화학식 VI로 표시되는 화합물을 합성한다. 산은 황산, 염산 또는 인산으로부터 선택될 수 있으며, 바람직하게 산은 황산이다. 염기는 수산화나트륨 또는 수산화칼륨으로부터 선택될 수 있으며, 바람직하게 염기는 수산화나트륨이다. In the step of hydrolyzing the compound represented by the formula (VI) to prepare the compound represented by the formula (II), the compound represented by the formula (VI) is synthesized through hydrolysis in the presence of an acid or a base. The acid may be selected from sulfuric acid, hydrochloric acid or phosphoric acid, preferably the acid is sulfuric acid. The base may be selected from sodium hydroxide or potassium hydroxide, preferably the base is sodium hydroxide.
화학식 II로 표시되는 화합물을 제조하는 단계는 산 조건에서는 40 내지 60 ℃에서 수행되는 것이 바람직하고 염기 조건에서는 환류 조건에서 수행되는 것이 바람직하다. The step of preparing the compound represented by the formula (II) is preferably carried out at 40 to 60 ° C under an acidic condition, and is preferably carried out under reflux condition at a base.
또한, 본 발명의 다른 구체예에 따르면 본 발명은, (A-1) 화학식 I로 표시되는 화합물과 화학식 IV로 표시되는 화합물을 반응시켜 화학식 V로 표시되는 화합물을 제조하는 단계; (A-2) 화학식 V로 표시되는 화합물에 2-요오드화벤조산(2-Iodobenzoic acid) 및 포타슘 퍼옥시모노설페이트(Potassium peroxymonosulfate)를 반응시켜 화학식 II로 표시되는 화합물을 제조하는 단계; 및 (A-3) 화학식 II로 표시되는 화합물을 고리화 반응시켜 화학식 III로 표시되는 화합물을 제조하는 단계를 포함하는 화학식 III로 표시되는 화합물의 제조방법을 제공한다. According to another embodiment of the present invention, there is provided a process for preparing a compound represented by the formula (I), comprising the steps of: (A-1) reacting a compound represented by the formula (I) with a compound represented by the formula (IV) (A-2) reacting a compound represented by the formula (V) with 2-iodobenzoic acid and potassium peroxymonosulfate to prepare a compound represented by the formula (II); And (A-3) cyclizing the compound represented by formula (II) to prepare a compound represented by formula (III).
상기 제조방법에서, 상기 (A-1) 및 (A-2) 단계는 앞에서 살핀 바와 같다. In the above production process, the steps (A-1) and (A-2) are as described above.
또한, 상기 (A-3) 단계는 산 조건 하에 고리화 반응이 수행될 수 있다. 상기 산은 황산, 염산 또는 인산으로부터 선택될 수 있으며, 바람직하게는 황산이다. 산 존재 하의 반응은 40 내지 60 ℃에서 반응되는 것이 바람직하다.Further, in the step (A-3), a cyclization reaction may be carried out under acidic conditions. The acid may be selected from sulfuric acid, hydrochloric acid or phosphoric acid, preferably sulfuric acid. The reaction in the presence of an acid is preferably carried out at 40 to 60 ° C.
또한, 본 발명의 다른 구체예에 따르면 본 발명은, (B-1) 화학식 I로 표시되는 화합물을 수산화구리를 이용하여 아크릴로니트릴과 반응시켜 화학식 VI로 표시되는 화합물을 제조하는 단계; (B-2) 화학식 VI로 표시되는 화합물을 가수분해하여 화학식 II로 표시되는 화합물을 제조하는 단계; 및 (B-3) 화학식 II로 표시되는 화합물을 고리화 반응시켜 화학식 III로 표시되는 화합물을 제조하는 단계를 포함하는 화학식 III로 표시되는 화합물의 제조방법을 제공한다. According to another embodiment of the present invention, there is provided a process for preparing a compound represented by formula (B-1), comprising the steps of: (B-1) reacting a compound represented by formula (I) with acrylonitrile using copper hydroxide to prepare a compound represented by formula (B-2) hydrolyzing a compound represented by the formula (VI) to prepare a compound represented by the formula (II); And (B-3) cyclizing the compound represented by formula (II) to prepare a compound represented by formula (III).
상기 제조 방법에서, 상기 (B-1) 및 (B-2) 단계는 앞에서 살핀 바와 같다. In the above production process, the steps (B-1) and (B-2) are as described above.
또한, 상기 (B-3) 단계는 산 조건 하에 고리화 반응이 수행될 수 있다. 반응 조건은 상기 (A-3) 단계의 내용이 적용될 수 있다. Further, in the step (B-3), the cyclization reaction may be carried out under an acidic condition. The contents of the step (A-3) may be applied to the reaction conditions.
한편, 화학식 VI로 표시되는 화합물에서 화학식 III로 표시되는 화합물로의 반응은 In-situ 반응으로 수행될 수 있다. On the other hand, the reaction of the compound represented by the formula (VI) with the compound represented by the formula (III) can be carried out by an in-situ reaction.
예를 들면, 본 발명에 따른 화학식 III로 표시되는 화합물의 제조방법은 하기 반응식 I로 표시될 수 있다. For example, a process for preparing a compound represented by formula (III) according to the present invention can be represented by the following reaction formula (I).
[반응식 I][Reaction Scheme I]
상기 반응식 I에서와 같이, 화학식 I로 표시되는 화합물부터 화학식 II로 표시되는 화합물의 제조는, 화학식 I로 표시되는 화합물에 화학식 IV로 표시되는 화합물을 처리하여 O-알킬화 반응을 수행한 후 2-요오드화벤조산(2-Iodobenzoic acid) 및 포타슘 퍼옥시모노설페이트(Potassium peroxymonosulfate)를 처리하여 화학식 II로 표시되는 화합물을 합성하거나, 아크릴로니트릴과 반응을 수행한 후 가수분해하여 제조할 수 있다. As in Scheme I, the preparation of the compound of formula (I) from the compound of formula (I) can be carried out by treating the compound of formula (I) with a compound of formula (IV) The compound of formula (II) may be synthesized by treating 2-iodobenzoic acid and potassium peroxymonosulfate, or may be reacted with acrylonitrile and hydrolyzed.
화학식 II로 표시되는 화합물로부터 화학식 III로 표시되는 화합물의 제조는, 산 존재 하에 화학식 II로 표시되는 화합물을 첨가한 후, 고리화 반응을 수행하여 제조할 수 있다. The preparation of the compound represented by the general formula (III) from the compound represented by the general formula (II) can be carried out by adding the compound represented by the general formula (II) in the presence of an acid, followed by carrying out a cyclization reaction.
본 발명에 따른 화학식 II로 표시되는 화합물의 제조방법은 하기 반응식 II-1로 표시될 수 있다. The method for preparing the compound represented by the formula (II) according to the present invention can be represented by the following Reaction Scheme II-1.
[반응식 II-1][Reaction Scheme II-1]
상기 반응식 II-1에서와 같이, 디메틸포름아미드 하에 화학식 I로 표시되는 화합물과 수소화나트륨을 반응시키고, 화학식 IV의 화합물과 O-알킬화 반응을 수행하여 화학식 V로 표시되는 화합물을 제조한다. 제조된 화학식 V로 표시되는 화합물을 2-요오드화벤조산 및 포타슘 퍼옥시모노설페이트와 반응시켜 화학식 II로 표시되는 화합물을 제조한다. As shown in Reaction Scheme II-1, a compound represented by the formula (V) is prepared by reacting a compound represented by the formula (I) with sodium hydride under dimethylformamide and performing an O-alkylation reaction with the compound represented by the formula (IV). The compound represented by the formula (V) is reacted with 2-iodobenzoic acid and potassium peroxymonosulfate to prepare a compound represented by the formula (II).
본 발명에 따른 화학식 II로 표시되는 화합물의 제조방법은 하기 반응식 II-2로 표시될 수 있다. The process for preparing the compound represented by the formula (II) according to the present invention can be represented by the following reaction formula II-2.
[반응식 II-2][Reaction Scheme II-2]
상기 반응식 II-2에서와 같이, 수산화구리 하에 아크릴로니트릴을 반응시켜 화학식 VI의 화합물을 제조하고, 산 처리를 통해 가수분해를 수행하여 화학식 II로 표시되는 화합물을 제조한다. As shown in Reaction Scheme II-2, acrylonitrile is reacted under copper hydroxide to prepare a compound represented by the formula (VI), and hydrolysis is carried out through an acid treatment to prepare a compound represented by the formula (II).
본 발명에 따른 화학식 III로 표시되는 화합물의 제조방법은 바람직하게 하기 반응식 I-1로 표시될 수 있다.The process for preparing a compound represented by formula (III) according to the present invention can be preferably represented by the following reaction scheme I-1.
[반응식 I-1][Reaction Scheme I-1]
상기 반응식 I-1에서와 같이, 디메틸포름아미드 하에 화학식 I로 표시되는 화합물과 수소화나트륨을 반응시키고, 화학식 IV의 화합물과 O-알킬화 반응을 수행하여 화학식 V로 표시되는 화합물을 제조한다. 제조된 화학식 V로 표시되는 화합물을 2-요오드화벤조산 및 포타슘 퍼옥시모노설페이트와 반응시켜 화학식 II로 표시되는 화합물을 제조한 후, 황산을 처리하여 고리화 반응을 통해 화학식 III로 표시되는 화합물을 제조한다. As shown in Reaction Scheme I-1, a compound represented by the formula (V) is prepared by reacting a compound represented by the formula (I) with sodium hydride under dimethylformamide and performing an O-alkylation reaction with the compound represented by the formula (IV). The compound represented by the formula (V) is reacted with 2-iodobenzoic acid and potassium peroxymonosulfate to prepare a compound represented by the formula (II), followed by treatment with sulfuric acid to produce a compound represented by the formula (III) do.
본 발명에 따른 화학식 III로 표시되는 화합물의 제조방법은 바람직하게 하기 반응식 I-2로 표시될 수 있다.The process for preparing a compound represented by the formula (III) according to the present invention can be preferably represented by the following reaction scheme I-2.
[반응식 I-2][Reaction Scheme I-2]
상기 반응식 I-2에서와 같이, 수산화구리 하에 아크릴로니트릴을 반응시켜 화학식 Ⅵ로 표시되는 화합물을 제조하고, 산 처리를 통해 가수분해를 수행한 후 고리화 반응을 진행하여 화학식 III로 표시되는 화합물을 제조한다. 여기서, 황산 처리 반응은 In-situ 반응으로 수행될 수 있다. As shown in Reaction Scheme I-2, acrylonitrile is reacted under copper hydroxide to prepare a compound represented by the general formula (VI), hydrolysis is carried out through an acid treatment, and the cyclization reaction proceeds to obtain the compound represented by the general formula (III) . Here, the sulfuric acid treatment can be performed in an in-situ reaction.
본 발명의 제조방법은 별도의 정제 공정이 필요하지 않고 낮은 제조 원가를 가지며, 환경 규제도 받지 않는 통상적으로 사용 가능한 시약과 용매를 사용하여 5,7-디플루오로크로만-4-온을 효과적으로 산업적으로 대량생산할 수 있다. The production method of the present invention is effective for the production of 5,7-difluorochroman-4-one effectively using commercially available reagents and solvents which do not require a separate purification step, have a low production cost, It can be mass-produced industrially.
이하, 하기 실시예 및 실험예를 통하여 본 발명을 보다 상세히 설명하고자 한다. 그러나, 하기 실시예 및 실험예는 본 발명을 예시하기 위한 것으로 이들 실시예 및 실험예에 의하여 본 발명의 범위가 한정되는 것은 아니다. Hereinafter, the present invention will be described in more detail with reference to the following examples and experimental examples. However, the following examples and experimental examples are provided for illustrating the present invention, and the scope of the present invention is not limited by these examples and experimental examples.
이하에서 언급된 시약 및 용매는 특별한 언급이 없는 한 Sigma Aldrich로부터 구입한 것이며, 1H-NMR는 Bruker NMR 400MHz로 측정하였다. The reagents and solvents mentioned below were purchased from Sigma Aldrich unless otherwise noted, and 1 H-NMR was measured by Bruker NMR 400 MHz.
실시예Example 1: 31: 3 -(3,5-- (3,5- 디플루오로페녹시Difluorophenoxy )프로판-1-올의 제조) Propan-1-ol < / RTI >
반응기에 수소화나트륨 36 kg과 디메틸포름아미드 439 kg을 투입하고, 0 ℃로 냉각하였다. 별도로 디메틸포름아미드 165 kg에 3,5-디플루오로페놀 116 kg을 용해시키고 5 ℃ 이하에서 반응기에 적가한 후 교반하였다. 또한, 디메틸포름아미드 165 kg에 3-클로로-1-프로판올 108 kg을 용해시키고 반응기에 적가한 후 80 ℃로 승온하여 반응하였다. 반응이 종결된 후 20 ℃로 냉각하고, 디이소프로필에테르 839 kg 및 정제수 530 kg을 투입하였다. 그 후 진한 염산 48 kg을 적가하고 교반하였다. 층 분리 후, 유기층에 5% 수산화나트륨 수용액(수산화나트륨 29 kg + 정제수 579 kg)을 투입하여 교반하고, 유기층을 분리하여 40 ℃에서 진공 농축하여 3-(3,5-디플루오로페녹시)프로판-1-올 (167 kg, 100 %, in-situ)을 수득하였다.36 kg of sodium hydride and 439 kg of dimethylformamide were added to the reactor and cooled to 0 占 폚. Separately, 116 kg of 3,5-difluorophenol was dissolved in 165 kg of dimethylformamide, dropped into the reactor at 5 ° C or lower, and then stirred. Further, 108 kg of 3-chloro-1-propanol was dissolved in 165 kg of dimethylformamide, added dropwise to the reactor, and the temperature was raised to 80 ° C to react. After the reaction was completed, the mixture was cooled to 20 DEG C, and 839 kg of diisopropyl ether and 530 kg of purified water were added. 48 kg of concentrated hydrochloric acid was then added dropwise and stirred. After separating the layers, an aqueous 5% sodium hydroxide solution (29 kg of sodium hydroxide + 579 kg of purified water) was added to the organic layer and stirred. The organic layer was separated and concentrated in vacuo at 40 ° C to give 3- (3,5- difluorophenoxy) Propan-1-ol (167 kg, 100%, in-situ).
1 H-NMR (400MHz, DMSO -d6): δ= 1.84 (quint, 2H), 3.54 (dd, 2H), 4.06 (t, 2H), 4.57 (t, 1H) 1 H-NMR (400MHz, DMSO -d6): δ = 1.84 (quint, 2H), 3.54 (dd, 2H), 4.06 (t, 2H), 4.57 (t, 1H)
실시예Example 2: 32: 3 -(3,5-- (3,5- 디플루오로페녹시Difluorophenoxy )) 프로파노익Propanoi 산의 제조 Manufacture of acid
반응기에 3-(3,5-디플로로펜옥시)프로판-1-올 167 kg, 아세토니트릴 882 kg 및 정제수 552 kg을 투입한 후 교반하고, 2-요오드화벤조산 11 kg 및 포타슘 퍼옥시모노설페이트 227 kg을 투입하여 80 ℃에서 교반하였다. 반응이 종결된 후에 5℃ 이하로 냉각하고 에틸아세테이트 1201 kg 및 정제수 1339 kg을 투입하여 교반하였다. 석출된 고체를 여과하고 에틸아세테이트 300 kg, 정제수 335 kg를 이용하여 세척하였다. 여과액을 40 ℃에서 진공 농축하고, 헵탄 569 kg을 투입하고 20 ℃로 냉각하여 교반하였다. 여과 후 40 ℃에서 진공건조하여 3-(3,5-디플로로펜옥시)프로파노익 산 (142 kg, 79 %)을 수득하였다. 167 kg of 3- (3,5-difluorophenoxy) propan-1-ol, 882 kg of acetonitrile and 552 kg of purified water were added to the reactor, stirred, and 11 kg of 2-iodobenzoic acid and potassium peroxymonosulfate 227 kg were added and stirred at 80 ° C. After the reaction was completed, the reaction mixture was cooled to 5 DEG C or lower, 1201 kg of ethyl acetate and 1339 kg of purified water were added thereto and stirred. The precipitated solid was filtered off and washed with 300 kg of ethyl acetate and 335 kg of purified water. The filtrate was concentrated in vacuo at 40 占 폚, charged with 569 kg of heptane, cooled to 20 占 폚 and stirred. After filtration and drying under vacuum at 40 캜, 3- (3,5-difluorophenoxy) propanoic acid (142 kg, 79%) was obtained.
1 H-NMR (400MHz, DMSO -d 6 ): δ= 2.69 (t, 2H), 4.19 (t, 2H), 6.68-6.81 (m, 3H), 12.4 (s, 1H) 1 H-NMR (400MHz, DMSO -d 6): δ = 2.69 (t, 2H), 4.19 (t, 2H), 6.68-6.81 (m, 3H), 12.4 (s, 1H)
실시예Example 3: 53: 5 ,7-, 7- 디플루오로크로만Difluorochroman -4-온의 제조-4-one
반응기 A에 진한 황산 345 kg을 투입하고, 10 ℃로 냉각하여 3-(3,5-디플로로펜옥시)프로파노익 산 142 kg을 적가하였다. 50 ℃에서 교반 후, 반응이 종결되면 20 ℃로 냉각시켰다. 반응기 B에 정제수 1421 kg을 투입하고, 0 ℃로 냉각하였다. 상기 반응기 A의 반응물을 10 ℃이하로 유지하면서 상기 반응기 B에 천천히 적가하고, 디클로로메탄 1890 kg을 가하고 교반하였다. 유기층을 분리 후, 정제수 1421 kg을 가하고 5% 탄산나트륨 수용액(탄산나트륨 14 kg + 정제수 284 kg)을 이용하여 pH 7.5를 맞췄다. 유기층을 분리하여 40 ℃에서 진공농축하고, 헵탄 483 kg을 투입하여 교반하였다. 여과 후 40 ℃에서 진공건조하여, 5,7-디플루오로크로만-4-온 (109 kg, 84 %)을 수득하였다. Reactor A was charged with 345 kg of concentrated sulfuric acid, cooled to 10 캜, and 142 kg of 3- (3,5-difluorophenoxy) propanoic acid was added dropwise. After stirring at 50 < 0 > C, the reaction was cooled to 20 < 0 > C. Reactor B was charged with 1421 kg of purified water and cooled to 0 占 폚. The reaction product of the reactor A was slowly added dropwise to the reactor B while maintaining the temperature at 10 ° C or lower, and 1890 kg of dichloromethane was added and stirred. After separating the organic layer, 1421 kg of purified water was added, and 5% aqueous sodium carbonate solution (sodium carbonate 14 kg + purified water 284 kg). The organic layer was separated, concentrated in vacuo at 40 占 폚, and 483 kg of heptane was added thereto and stirred. After filtration and vacuum drying at 40 DEG C, 5,7-difluorochroman-4-one (109 kg, 84%) was obtained.
1 H-NMR (400MHz, DMSO -d 6 ): δ= 2.77 (t, 2H), 4.57 (t, 2H), 6.81-6.95 (m, 2H) 1 H-NMR (400MHz, DMSO -d 6): δ = 2.77 (t, 2H), 4.57 (t, 2H), 6.81-6.95 (m, 2H)
실시예Example 4: 34: 3 -(3,5-- (3,5- 디플루오로페녹시Difluorophenoxy )) 프로판니트릴의Propanenitrile 제조 Produce
반응기에 3,5-디플루오로페놀 13 kg과 아크릴로니트릴 21 kg을 투입 후 교반하였다. 수산화구리 5 kg을 투입하고 80 ℃에서 48 시간 동안 환류하였다. 반응 종결 후 상온으로 냉각하고, 50 ℃에서 농축하였다. 디클로로메탄 100 L와 정제수 50 L을 투입하고 교반하였다. 유기층에 정제수 50 L를 투입 후, 교반하여 유기층을 분리하였다. 그 후, 무수 황산마그네슘을 이용하여 건조하고 용매를 감압 제거함으로써 3-(3,5-디플루오로페녹시)프로판니트릴 (11 kg, 60 %)을 수득하였다. 13 kg of 3,5-difluorophenol and 21 kg of acrylonitrile were added to the reactor and stirred. 5 kg of copper hydroxide was added and refluxed at 80 ° C for 48 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated at 50 캜. 100 L of dichloromethane and 50 L of purified water were added and stirred. 50 L of purified water was added to the organic layer, followed by stirring to separate the organic layer. Thereafter, the organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure to obtain 3- (3,5-difluorophenoxy) propanenitrile (11 kg, 60%).
1 H-NMR (400MHz, CDCl 3 ): δ= 2.87 (t, 2H), 4.19 (t, 2H), 6.44-7.54 (m, 3H) 1 H-NMR (400MHz, CDCl 3): δ = 2.87 (t, 2H), 4.19 (t, 2H), 6.44-7.54 (m, 3H)
실시예Example 5: 55: 5 ,7-, 7- 디플루오로크로만Difluorochroman -4-온의 제조-4-one
반응기 A에 진한 황산 30 kg을 투입하였다. 3-(3,5-디플루오로페녹시)프로판니트릴 11 kg을 10~20 ℃에서 투입하고, 50 ℃로 승온하여 교반하였다. 반응이 완결되면 상온으로 냉각하였다. 반응기 B에 정제수 100 L에 투입하고 0 ℃로 냉각하였다. 반응기 A의 반응물을 반응기 B에 투입하였다. 디클로로메탄 110 L을 투입하고, 5% 탄산나트륨 수용액을 이용하여 pH 7로 조절하였다. 교반 후 유기층을 분리하였다. 감압농축 후 헵탄 55 L을 투입하고 교반 후 여과하였다 40 ℃에서 진공건조하여 5,7-디플루오로크로만-4-온 (9 kg, 80 %)을 수득하였다. 30 kg of concentrated sulfuric acid was introduced into the reactor A. 11 kg of 3- (3,5-difluorophenoxy) propanenitrile was added thereto at 10 to 20 ° C, and the mixture was heated to 50 ° C and stirred. When the reaction was completed, the reaction solution was cooled to room temperature. Reactor B was charged with 100 L of purified water and cooled to 0 占 폚. Reactor A was charged to Reactor B. 110 L of dichloromethane was added thereto, and the pH was adjusted to 7 using a 5% aqueous sodium carbonate solution. After stirring, the organic layer was separated. After concentrating under reduced pressure, 55 L of heptane was added, stirred, and filtered. Vacuum drying at 40 ° C yielded 5,7-difluorochroman-4-one (9 kg, 80%).
1 H-NMR (400MHz, CDCl 3 ): δ= 2.81 (t, 2H), 4.55 (t, 2H), 6.44-6.53 (m, 2H) 1 H-NMR (400MHz, CDCl 3): δ = 2.81 (t, 2H), 4.55 (t, 2H), 6.44-6.53 (m, 2H)
Claims (13)
(A-2) 화학식 V로 표시되는 화합물에 2-요오드화벤조산(2-Iodobenzoic acid) 및 포타슘 퍼옥시모노설페이트(Potassium peroxymonosulfate)를 반응시켜 화학식 II로 표시되는 화합물을 제조하는 단계; 및
(A-3) 화학식 II로 표시되는 화합물을 고리화 반응시켜 화학식 III로 표시되는 화합물을 제조하는 단계를 포함하는 화학식 III로 표시되는 화합물의 제조방법:
[화학식 I]
[화학식 II]
[화학식 III]
[화학식 IV]
[화학식 V]
상기 화학식 Ⅳ에서, X는 F, Cl 또는 I 임.(A-1) reacting a compound represented by the formula (I) with a compound represented by the following formula (IV) to prepare a compound represented by the formula (V)
(A-2) reacting a compound represented by the formula (V) with 2-iodobenzoic acid and potassium peroxymonosulfate to prepare a compound represented by the formula (II); And
(A-3) a process for producing a compound represented by the formula (III) which comprises the step of cyclizing a compound represented by the formula (II) to prepare a compound represented by the formula (III)
(I)
≪ RTI ID = 0.0 &
(III)
(IV)
(V)
In the above formula (IV), X is F, Cl or I.
(B-2) 화학식 VI로 표시되는 화합물을 가수분해하여 화학식 II로 표시되는 화합물을 제조하는 단계; 및
(B-3) 화학식 II로 표시되는 화합물을 고리화 반응시켜 화학식 III로 표시되는 화합물을 제조하는 단계를 포함하는 화학식 III로 표시되는 화합물의 제조방법:
[화학식 I]
[화학식 II]
[화학식 III]
[화학식 VI]
(B-2) hydrolyzing a compound represented by the formula (VI) to prepare a compound represented by the formula (II); And
(B-3) a process for producing a compound represented by the formula (III) which comprises the step of cyclizing a compound represented by the formula (II) to prepare a compound represented by the formula (III)
(I)
≪ RTI ID = 0.0 &
(III)
(VI)
13. The method according to claim 12, wherein the acid is any one selected from sulfuric acid, hydrochloric acid, and phosphoric acid.
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| US4625042A (en) * | 1984-07-09 | 1986-11-25 | Kanegafuchi Kagaku Kogyo Kabushiki Kaisha | Process for preparing 6-fluoro-4-chromanone using 3-(4-fluorophenoxy)propionitrile |
| WO2005016896A1 (en) | 2003-08-08 | 2005-02-24 | Janssen Pharmaceutica, N.V. | 2- (quinoxalin-5-ylsulfonylamino) -benzamide compounds as cck2 modulators |
| WO2009156072A1 (en) | 2008-06-25 | 2009-12-30 | Bayer Schering Pharma Aktiengesellschaft | Substituted 7-sulfanylmethyl, 7-sulfinylmethyl and 7-sulfonylmethyl indoles and use thereof |
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| US4625042A (en) * | 1984-07-09 | 1986-11-25 | Kanegafuchi Kagaku Kogyo Kabushiki Kaisha | Process for preparing 6-fluoro-4-chromanone using 3-(4-fluorophenoxy)propionitrile |
| WO2005016896A1 (en) | 2003-08-08 | 2005-02-24 | Janssen Pharmaceutica, N.V. | 2- (quinoxalin-5-ylsulfonylamino) -benzamide compounds as cck2 modulators |
| KR20060060007A (en) * | 2003-08-08 | 2006-06-02 | 얀센 파마슈티카 엔.브이. | 2- (quinoxalin-5-ylsulfonylamino)-benzamide compounds as cck2 modulators |
| WO2009156072A1 (en) | 2008-06-25 | 2009-12-30 | Bayer Schering Pharma Aktiengesellschaft | Substituted 7-sulfanylmethyl, 7-sulfinylmethyl and 7-sulfonylmethyl indoles and use thereof |
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| KR102459196B1 (en) | 2022-04-08 | 2022-10-27 | 케이블루바이오 주식회사 | A Composition for Preventing or Treating Multiple Myeloma Comprising Novel Chromanone Compounds as Active Ingredients |
| KR20230145899A (en) | 2022-04-08 | 2023-10-18 | 케이블루바이오 주식회사 | A Composition for Preventing or Treating Multiple Myeloma Comprising Novel Chromanone Compounds as Active Ingredients |
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